Efficacy and Safety of Mesenchymal Stem Cell Therapy in Chronic Limb-Threatening Ischemia: A Meta-analysis of Randomized Controlled Trials

Nabil Athoillah (Faculty of Medicine, Jember University, Jember, Indonesia)
Arya Marganda Simanjuntak (Faculty of Medicine, Riau University, Arifin Achmad General Hospital, Riau, Indonesia)
Mitsla Chusnica Aulia As’Ar (Master Program in Biomedical Sciences, School of Postgraduate Studies, Hasanuddin University, Makassar, Indonesia)
Dimas Widyadhana Bhanu Aryasatya (Faculty of Medicine, Jember University, Jember, Indonesia)
Lunggita Arabela Sugiarto (Faculty of Medicine, Jember University, Jember, Indonesia)
Hazna Fridella Utomo (Faculty of Medicine, Jember University, Jember, Indonesia)
Meutia Citra Aisya (Faculty of Medicine, Jember University, Jember, Indonesia)
Kevin Sanjaya Listiono (Faculty of Medicine, Tarumanagara University, Jakarta, Indonesia)
Ayu Diajeng Sekar Negari (Departement of Cardiovascular, Syarifah Ambami Rato Ebu Regional Hospital, Bangkalan, Indonesia)
Yusfik Helmi Hidayat (Departement of Surgery, Syarifah Ambami Rato Ebu Regional Hospital, Bangkalan, Indonesia)
Aditha Satria Maulana (Department of Cardiovascular, Faculty of Medicine, Jember University - Dr. Soebandi General Hospital, Jember, Indonesia)

Indonesian Journal of Cardiology
Online First

Background: Chronic Limb-Threatening Ischemia (CLTI) represents the terminal stage of peripheral artery disease, carrying substantial morbidity and mortality. Despite various therapeutic strategies, clinical outcomes remain unsatisfactory, highlighting the urgent need for novel treatments. While Mesenchymal Stem Cells (MSCs) show promise at the cellular level, human studies are limited, preventing generalizable conclusions at this time. This study aimed to systematically assess the efficacy and safety of MSCs implantation in CLTI. Methods: PRISMA 2020-guided meta-analysis of intervention. Various databases were searched using keywords based of the PICOS framework. The PICOS framework guided our approach: Patients (CLTI), Intervention (MSCs), Comparison (Placebo OR Control), Outcome (Amputation, Ulcer Healing Rate, Rest Pain Change, Ankle-Brachial Index, Adverse Effect), and Study (Randomized Controlled Trial [RCT]). Statistical analysis was performed using Review Manager (RevMan 5.4.1) and RStudio (R.4.4.3). An Independent Risk-of-Bias 2 (RoB2) risk of bias assessment was performed. Results: Seven RCTs were included with a total of 270 patients. Meta-analysis showed that MSCs were more effective than the control group on suppressing the amputation rate (Odds Ratio [OR] = 0.40, 95% Confidence Interval [CI] = 0.17–0.95, p = 0.04). Ulcer healing rate was significantly higher in the MSCs therapy group compared to the control group (OR = 9.79, 95% CI = 2.59–36.98, p = 0.0008). Moreover, MSCs therapy markedly improved clinical outcomes, including rest pain score (Mean Difference [MD] = –1.88, 95% CI = –2.93 to –0.84, p = 0.0004) and ankle-brachial index (MD = 0.16, 95% CI = 0.09–0.22, p < 0.00001). Interestingly, MSCs therapy showed an excellent safety profile, with negligible gastrointestinal-hepatobiliary events and only 4% mild infections or musculoskeletal effects. Conclusion: This review shows that MSCs therapy offers a transformative approach for CLTI, significantly improving limb outcomes and perfusion while maintaining an excellent safety profile.